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AIM: To observe the effect of fudosteine on induced sputum cell components and lung function in patients with stable neutrophil-dominated COPD. METHODS: From October 2019 to October 2022, 53 patients with stable COPD were selected and divided into fudosteine group and placebo group. The placebo group was treated with routine treatment, and the fudosteine group was treated with fudosteine on the basis of routine treatment. The two groups were treated for 6 months. The clinical symptoms [Saint George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT) and Modified British Medical Research Council Dyspnea scale (MMRC), Breathlessness, Cough, and Sputum Scale (BCSS)], lung function index, induced sputum cytology analysis and other related examination results were recorded in detail before and after treatment. RESULTS: (1) Compared with the baseline, the forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and the ratio of FEV1 to FVC (FEV1/FVC) of the two groups were improved after treatment, and the differences were statistically significant (P<0.05). However, after treatment, there was no significant difference in pulmonary function between the two groups except for the percentage of carbon monoxide diffusion in the predicted value (DLCO%pre) (DLCO%pre in the fudosteine group was higher than that in the placebo group). (2) After treatment, the total number of induced sputum cells and neutrophil counts in the fudosteine group were lower than those in the placebo group. Compared with the number of cells in each component at baseline, the total number of induced sputum cells and neutrophil count in the fudosteine group were significantly lower (P< 0.05). CONCLUSION: Fudosteine treatment in patients with stable neutrophil-dominated COPD can improve lung function, reduce the total number of induced sputum cells and the total number of neutrophils, thereby improving airway inflammation.
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GC-MS metabolomics was used to investigate the effects of fudosteine on lung cancer A549 cells in an inflammatory microenvironment. Eleven metabolites (malic acid, isoleucine, lactose, galactinol, creatinine, gluconic acid, oleic acid, phosphate, S-carboxymethyl-L-cysteine, uridine and tagatose) were identified in the metabolomics results and could be used as biomarkers of fudosteine treatment. Pathway enrichment analysis showed that the metabolic pathways of amino acids including isoleucine, valine, leucine, glycine, serine and threonine were significantly altered, as were the metabolic pathways of carbohydrates such as galactose and pentose phosphate. Fudosteine significantly reduced the level of inflammatory factors in A549 cells and corrected the inflammatory microenvironment by interfering with the effects of amino acid metabolites and amino acid metabolism pathways. This study reveals that fudosteine may be able to inhibit the continuous inflammatory response and prevent the further progression of lung cancer by suppressing the inflammatory microenvironment.
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OBJECTIVE： To establish the method for content determination of the related substance in fudosteine raw material and its preparations. METHODS： Fudosteine or its preparations produced by 8 domestic enterprises were taken as samples. HPLC method （external standard） was used to determine the contents of impurities A， B and C. The separation was performed on MGⅡ C18 column with mobile phase consisted of 0.12％ sodium hexane sulfonate solution （pH 2.0） at flow rate of 1.0 mL/min. The detection wavelength was set at 210 nm， column temperature was 35 ℃ and sample size was 20 μL. The contents of impurities E， F， G were determined by HPLC method （principal component self-contrast method with correction factor）. The separation was performed on Altech Altima C18 column with mobile phase consisted of 0.05 mol/L phosphate buffer-acetonitrile- water （gradient elution） at the flow rate of 0.5 mL/min. The detection wavelength was set at 200 nm， and the column temperature was 30 ℃. The sample size was 20 μL. RESULTS： The linear ranges of impurity A， B， C， E， F and G were 0.446-22.291， 0.202-20.158， 0.101-12.082， 0.111 0-11.100， 0.210 4-10.520， 0.221 6-11.080 μg/mL， respectively. The limits of detection were 5.57， 1.01， 1.99， 2.22， 4.21， 4.43 ng， respectively. The limits of quantitation were 11.14， 2.02， 3.98， 4.45， 8.42， 8.85 ng， respectively. The relative correction factors of impurities E， F and G were 0.91， 1.42 and 1.73， respectively； their relative retention time were 0.88， 1.95 and 3.08. RSDs of precision （n＝6） and stability [impurity A （4 h，n＝3）， other impurities （24 h，n＝7）] tests were all lower than 2.0％. The average recoveries were 98.0％， 97.3％， 102.4％， 99.4％， 98.9％， 96.4％， respectively； RSDs were 1.4％， 1.5％， 1.1％， 0.9％， 1.2％， 0.5％ （n＝9）， respectively. Total contents of substances in fudosteine raw material or its preparation produced by 8 enterprises were all lower than 1.1％. CONCLUSIONS： Established method is sensitive and specific. The method can be used for the quantitative study on related substances in fudosteine raw material and its preparations．
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To study the substances in fudosteine, one synthetic by-product and five forced degradation products were detected by hydrophilic interaction chromatography (HILIC). Quadrupole-time-of-flight mass spectrometry (Q-TOF MS) was used for accurate mass determination and product ion scanning. Five related substances were identified in the products of mass spectra fragmentations elucidation, and verified further according to synthetic process and stress testing results. The results obtained are valuable for fudosteine manufacturing process control and quality assurance.
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BACKGROUND: Fudosteine, (-)-(R)-2-amino-3-(3-hydroxypropylthio)propionic acid, is a cysteine derivative that was approved in Japan, as a new mucoactive agent. The aim of this study was to evaluate the tolerability and pharmacokinetics (PK) of fudosteine in healthy Korean subjects. METHODS: A randomized, open-label, parallel, escalating single-dose study was conducted in 16 healthy Korean male subjects. The subjects were allocated to single-dose groups of 400 or 800 mg. Serial blood samples for PK analysis were collected immediately prior and after dosing up to 24 hours, and plasma concentrations were determined by high performance liquid chromatography (HPLC). Safety profiles were evaluated by monitoring adverse events and clinical evaluations throughout the study. RESULTS: Median time to peak concentration (Tmax) of both dosing group were around 0.5 hours and half-life (t1/2) were around 3 hours. Mean peak concentration (Cmax) of 400 mg and 800 mg dosing group were 10.8 and 21.5 microg/mL and the mean area under the plasma concentration versus time curve from the dosing time to infinity (AUCinf) were 26.8 and 55.0 microg.h/mL, respectively. Mean dose-normalized Cmax were 0.0271 and 0.0269 microg/mL/mg (P=0.923), respectively and dose-normalized AUCinf were 0.0669 and 0.0688 microg.hr/mL/mg (P=0.093), respectively. Fudosteine was well tolerated without any serious adverse events or clinical laboratory abnormalities. CONCLUSION: This study showed that fudosteine has a linear PK property and is well tolerated within 800 mg in healthy Korean volunteers.